The present invention relates to bicyclic amino derivatives and prostaglandin D2 (hereinafter, referred to as PGD2) antagonist containing them.
Some of bicyclic amino derivatives of the present invention have known to be useful as thromboxane A2 (TXA2) antagonists (Japanese Patent Publication (KOKOKU) No. 79060/1993). However, the Japanese Patent Publication (KOKOKU) No. 79060/1993 only describes that the compounds are useful as TXA2 antagonist, and does not suggest the usefulness thereof as PGD2 antagonist as disclosed by the present invention.
Namely, the TXA2 is known to have activities such as action against platelet agglutination, thrombogenesis, etc. The TXA2 antagonist has therefore been considered to be useful as anti-thrombotic agent, and also in the treatment of myocardial infarction or asthma by antagonizing against TXA2.
On the other hand, the PGD2 antagonist of the present invention is useful in the improvement of conditions due to excessive production of PGD2. Specifically, it is useful as a drug for treating diseases in which mast cell dysfunction is involved, for example, systemic mastocytosis and disorder of systemic mast cell activation, and also tracheal contraction, asthma, allergic rhinitis, allergic conjunctivitis, urticaria, injury due to ischemic reperfusion, and inflammation.
As is apparent from the above, the TXA2 antagonist and the PGD2 antagonist are completely different from each other in terms of the active site, mechanism of action, and application, and have quite different characteristics. Accordingly, it has never been expected that any compound could possess these activities simultaneously.
PGD2 is produced through PGG2 and PGH2 from arachidonic acid by the action of cyclooxygenase activated by immunological or unimmunological stimulation and is the major prostanoid that is produced and released from mast cells. PGD2 has various potent physiological and pathological activities. For example, PGD2 can cause strong tracheal contraction, which leads to bronchial asthma, and, in a systemic allergic state, it can dilate the peripheral vessels, which leads to an anaphylactic shock. Especially, much attention has been paid on the idea that PGD2 is one of the causal substances responsible to the onset of nasal occlusion in the allergic rhinitis. Therefore, it has been proposed to develop an inhibitor against the biosynthesis of PGD2 or an antagonist of PGD2 receptor as a drug for the reduction of nasal occlusion. However, the inhibitor of PGD2 biosynthesis possibly affects greatly the synthesis of prostaglandins in other organisms, and therefore, it is desirable to develop an antagonist (blocker) specific to PGD2 receptor.
The present inventors have studied intensively to develop PGD2 receptor antagonists (blockers) specific to PGD2 receptor, and found that compounds of the formula (I) below or its salt possess a potent activity as PGD2 receptor antagonist, and are chemically and biochemically stable.
Accordingly, the present invention provides a PGD2 antagonist which comprises a compound of the general formula (I) below or its salt or a hydrate thereof as an active ingredient: 
wherein: 
A is alkylene which optionally is intervened by hetero atom or phenylene, contains oxo group, and/or has an unsaturated bond;
B is hydrogen, alkyl, aralkyl or acyl;
R is COOR1, CH2OR2 or CON(R3)R4;
R1 is hydrogen or alkyl;
R2 is hydrogen or alkyl;
R3 and R4 each are independently hydrogen, alkyl, hydroxy or alkylsulfonyl;
X1 is a single bond, phenylene, naphtylene, thiophenediyl, indolediyl, or oxazolediyl;
X2 is a single bond, xe2x80x94Nxe2x95x90Nxe2x80x94, xe2x80x94Nxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90Nxe2x80x94, xe2x80x94CHxe2x95x90Nxe2x80x94Nxe2x80x94, xe2x80x94CHxe2x95x90Nxe2x80x94Oxe2x80x94, xe2x80x94Cxe2x95x90NNHCSNHxe2x80x94, xe2x80x94Cxe2x95x90NNHCONHxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH(OH)xe2x80x94, xe2x80x94C(Cl)xe2x95x90C(Cl)xe2x80x94, xe2x80x94(CH2)n-, ethynylene, xe2x80x94N(R5)xe2x80x94, xe2x80x94N(R51)COxe2x80x94, xe2x80x94N(R52)SO2xe2x80x94, xe2x80x94N(R53)CON(R54)xe2x80x94, xe2x80x94CON(R55)xe2x80x94 xe2x80x94SO2N(R56)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94COxe2x80x94, oxadiazolediyl, thiadiazolediyl or tetrazolediyl;
X3 is alkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclic group, cycloalkyl, cycloalkenyl, thiazolinylidenemethyl, thiazolidinylidenemethyl, xe2x80x94CHxe2x95x90NR6 or xe2x80x94Nxe2x95x90C(R7)R3;
R5, R51, R52, R53, R54, R55 and R56 each are hydrogen or alkyl;
R6 is hydrogen, alkyl, hydroxy, alkoxy, carbamoyloxy, thiocarbamoyloxy, ureido or thioureido;
R7 and R8 each are independently alkyl, alkoxy or aryl;
n is 1 or 2;
Z is xe2x80x94SO2xe2x80x94 or xe2x80x94COxe2x80x94; and
m is 0 or 1;
wherein a cyclic substituent may has one to three substituents selected from the group consisting of nitro, alkoxy, sulfamoyl, substituted- or unsubstituted-amino, acyl, acyloxy, hydroxy, halogen, alkyl, alkynyl, carboxy, alkoxycarbonyl, aralkoxycarbonyl, aryloxycarbonyl, mesyloxy, cyano, alkenyloxy, hydroxyalkyl, trifluoromethyl, alkylthio, xe2x80x94Nxe2x95x90PPh3, oxo, thioxo, hydroxyimino, alkoxyimino, phenyl and alkylenedioxy.
Specific examples of compounds usable as a PGD2 antagonist above include a compound of the formula (I) wherein: 
is 
m is 0; and when Z is SO2, both X1 and X2 are a single bond; X3 is alkyl, phenyl, naphthyl, stylyl, quinolyl or thienyl; and a cyclic substituent among these substituents optionally has one to three substituents selected from a group consisting of nitro, alkoxy, substituted- or unsubstituted-amino, halogen, alkyl and hydroxyalkyl, or its salt or hydrate thereof.
Similarly, specific examples include a compound of the formula (I) wherein: 
when m is 1, both X1 and X2 are a single bond; and X3 is phenyl optionally substituted with halogen, or its salt or hydrate thereof.
Similarly, specific examples include a compound of the formula (I) wherein: 
when m is 1, X1 is phenyl, X2 is xe2x80x94CH2xe2x80x94 or xe2x80x94Nxe2x95x90Nxe2x80x94 and X3 is phenyl, or its salt or hydrate thereof.
Similarly, examples of compounds of the formula (I) include those of the formula (Ia): 
wherein A, B, R, X1, X2 and X3 are as defined above, or its salt or hydrate thereof, provided that those wherein (1) X1 and X2 are a single bond, and X3 is substituted- or unsubstituted-phenyl, or naphthyl; and (2) A is 5-heptenylene, R is COOR1 (R1 is hydrogen or methyl), X1 is 1,4-phenylene, X2 is a single bond, and X3 is phenyl are excluded.
Similarly, examples of compounds of the formula (I) include those of the formula (Ib): 
wherein: 
A, B, R, X1, X2 and X3 are as defined above, or its salt or hydrate thereof, provided that those wherein X1 and X2 are a single bond, and X3 is phenyl, and wherein X1 is a single bond, X2 is xe2x80x94Oxe2x80x94, and X3 is benzyl are excluded.
More specifically, examples of compounds of the formula (I) include those of the formula (Ia) wherein X1 and X2 are a single bond, X3 is isoxazolyl, thiadiazolyl, isothiazolyl, morpholyl, indolyl, benzofuryl, dibenzofuryl, dibenzodioxinyl, benzothienyl, dibenzothienyl, carbazolyl, xanthenyl, phenanthridinyl, dibenzoxepinyl, dibenzothiepinyl, cinnolyl, chromenyl, benzimidazolyl or dihydrobenzothiepinyl, or its salt or hydrate thereof.
Similarly, examples of compounds of the formula (I) include those of the formula (Ia) wherein X1 is a single bond, X2 is phenylene, X3 is alkenyl, alkynyl, xe2x80x94CHxe2x95x90NR6 or xe2x80x94Nxe2x95x90C(R7)R8, or its salt or hydrate thereof.
Similarly, examples of compounds of the formula (I) include those of the formula (Ia) wherein R is COOR1, X1 is phenylene or thiophenediyl, X2 is a single bond, xe2x80x94Nxe2x95x90Nxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CONHxe2x80x94, xe2x80x94NHCOxe2x80x94 or ethynylene and X3 is phenyl, thiazolinylidenemethyl, thiazolidinylidenemethyl or thienyl, or its salt or hydrate thereof.
More specifically, examples of the compound (I) of the present invention include those of the formula (Ib) wherein: 
is 
or its salt orhydrate thereof. Examples of more preferred compounds include those of the formula (Ib) wherein R is COOR1 (R1 is as defined above) or its salt or hydrate thereof.
Similarly, examples of compound (I) include those of the formula (Ib) wherein X1 is phenylene or thiophenediyl, X2 is a single bond, xe2x80x94Nxe2x95x90Nxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, ethynylene, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94CON(R55)xe2x80x94 (R55 is as defined above), xe2x80x94N(R51)COxe2x80x94 (R51 is as defined above) and X3 is phenyl, or its salt or hydrate thereof.
More specifically, examples of compound (I) include those of the formula (Ib) wherein: 
or its salt or hydrate thereof. Examples of more preferred embodiment include those wherein B is hydrogen, both X1 and X2 are a single bond, X3 is thienyl, thiazolyl, thiadiazolyl, isothiazolyl, pyrrolyl, pyridyl, benzofuryl, benzimidazolyl, benzothienyl, dibenzofuryl, dibenzothienyl, quinolyl or indolyl or its salt or hydrate thereof. Similarly, examples include those wherein X1 is phenylene, thiophenediyl, indolediyl or oxazolediyl, X2 is a single bond, xe2x80x94Nxe2x95x90Nxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, ethynylene, xe2x80x94Sxe2x80x94 or xe2x80x94Oxe2x80x94, and X3 is aryl or heterocyclic group, or its salt or hydrate thereof.
The compounds of the general formula (Ia) and (Ib) are novel compounds synthesized by the present inventors.
The terms used throughout the present specification are as defined below.
The term xe2x80x9calkyleneuxe2x80x9d means C1-C9 straight or branched chain alkylene, for example, methylene, methylmethylene, dimethylmethylene, methylethylmethylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethyene, nonamethylene, or the like. The alkylene above can be intervened by a hetero atom(s) (oxygen, sulfur, nitrogen atom, or the like) or phenylene (e.g., 1,4-phenylene, 1,3-phenylene, 1,2-phenylene, or the like), contain an oxo group, and/or have one or more double- or triple-bonds at any positions on the chain. Examples include xe2x80x94(CH2)2xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94Oxe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)2xe2x80x94Oxe2x80x94(CH2)3xe2x80x94, xe2x80x94(CH2)2xe2x80x94Oxe2x80x94(CH2)4xe2x80x94, xe2x80x94(CH2)2xe2x80x94Oxe2x80x94(CH2)5xe2x80x94, xe2x80x94(CH2)2xe2x80x94Oxe2x80x94(CH2)6xe2x80x94, xe2x80x94(CH2)2xe2x80x94Sxe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)3xe2x80x94Sxe2x80x94(CH2)2xe2x80x94, xe2x80x94CH2xe2x80x94Sxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94Sxe2x80x94(CH2)4xe2x80x94, xe2x80x94CH2xe2x80x94N(CH3)xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94NHxe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)2xe2x80x94N(CH2CH3)xe2x80x94(CH2)3xe2x80x94, xe2x80x94(CH2)2-1,4-phenylene-CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94O-1,3-phenylene-CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94O-1,2-phenylene-CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94O-1,4-phenylene-CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94Sxe2x80x94CH2-1,4-phenylene-CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94S-1,3-phenylene-(CH2)2xe2x80x94, 2-oxopropylene, 3-oxbpentylene, 5-oxohexylene, vinylene, 1-propenylene, 2-propenylene, 1-butenylene, 2-butenylene, 3-butenylene, 1,2-butadienylene, 1,3-butadienylene, 1-pentenylene, 2-pentenylene, 3-pentenylene, 4-pentenylene, 1,2-pentadienylene, 1,3-pentadienylene, 1,4-pentadienylene, 2,3-pentadienylene, 2,4-pentadienylene, 1-hexyenylene, 2-hexenylene, 3-hexenylene, 4-hexenylene, 5-hexenylene, 1,2-hexadienylene, 1,3-hexadienylene 1,4-hexadienylene, 1,5-hexadienylene, 2,3-hexadienylene, 2,4-hexadienylene 2,5-hexadienylene, 3,4-hexadienylene, 3,5-hexadienylene, 4,5-hexadienylen, 1,1-dimethyl-4-hexenylen, 1-heptenylene, 2-heptenylene, 3-heptenylene, 4-heptenylene, 5-heptenylene, 2,2-dimethyl-5-heptenylene, 6-heptenylene, 1,2-heptadienylene, 1,3-heptadienylene, 1,4-heptadienylene, 1,5-heptadienylene, 1,6-heptadienylene, 2,3-heptadienylene, 2,4-heptadienylene, 2,5-heptadienylene, 2,6-heptadienylene, 3,4-heptadienylene, 3,5-heptadienylene, 3,6-heptadienylene, 4,5-heptadienylene, 4,6-heptadienylene or 5,6-heptadienylene, 1-propynylene, 3-butynylene, 2-pentynylene, 5-hexynylene, 6-heptynylene, xe2x80x94(CH2)xe2x80x94CHxe2x95x90CHxe2x80x94Oxe2x80x94(CH2)2xe2x80x94, xe2x80x94CH2xe2x80x94Sxe2x80x94(CH2)3xe2x80x94, xe2x80x94CH2-cis-CHxe2x95x90CH-1,2-phenylene-CH2xe2x80x94, xe2x80x94CHxe2x95x90CH-1,4-phenylene-(CH2)2xe2x80x94, -4-oxo-4,5-hexenylene-, and the like.
The term xe2x80x9calkylxe2x80x9d means C1-C20 straight or branched chain alkyl, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, neopentyl, t-pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl, and the like.
The term xe2x80x9carylxe2x80x9d means C6-C14 monocyclic or condensed ring, for example, phenyl, naphthyl (e.g., 1-naphthyl, 2-naphtyl), anthryl (e.g., 1-anthryl, 2-anthryl, 9-anthryl), phenanthryl (e.g., 2-phenanthryl, 3-phenanthryl, 9-phenanthryl), fluorenyl (e.g., 2-fluorenyl), and the like. Phenyl is especially preferred.
The term xe2x80x9caralkylxe2x80x9d means a group formed by substituting an alkyl as defined above with an aryl above at any substitutable positions on the alkyl. Examples include benzyl, phenethyl, phenylpropyl (e.g., 3-phenylpropyl), naphtylmethyl (e.g., xcex1-naphtylmethyl), anthrylmethyl (e.g., 9-anthrylmethy), phenanthrylmethyl (e.g., 3-phenanthrylmethyl), and the like.
The term xe2x80x9cacylxe2x80x9d means C1-C9 acyl derived from aliphatic carboxylic acid, for example, formyl, acetyl, propionyl, butyryl, valeryl, and the like.
The term xe2x80x9calkylsulfonylxe2x80x9d means a group formed by substituting a sulfonyl with an alkyl above, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, and the like.
The term xe2x80x9calkenylxe2x80x9d is C2-C20 straight or branched chain alkenyl, which corresponds to an alkyl above containing one or more double bonds. Examples include vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,2-butadienyl, 1-pentenyl, 1,2-pentadienyl, 2-hexyenyl, 1,2-hexadienyl, 3-heptenyl, 1,5-heptadienyl, and the like.
The term xe2x80x9calkynylxe2x80x9d is C2-C20 straight or branched chain, alkynyl, which corresponds to an alkyl above containing one or more triple bonds. Examples include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, and the like.
The term xe2x80x9cheterocyclic groupxe2x80x9d means 5-7 membered cyclic group containing one or more hetero atoms selected independently from the group consisting of oxygen, sulfur and/or nitrogen atom on the ring, and is optionally condensed with a carbon ring or other heterocyclic group at any substitutable positions. Examples include pyrrolyl (e.g., 1-pyrrolyl, 3-pyrrolyl), indolyl (e.g., 2-indolyl, 3-indolyl, 6-indolyl), carbazolyl (e.g., 2-carbazolyl, 3-carbazolyl), imidazolyl (e.g., 1-imidazolyl, 4-imidazolyl), pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl), benzimidazolyl (e.g., 2-benzimidazolyl, 5-benzimidazolyl), indazolyl (e.g., 3-indazolyl), indolizinyl (e.g., 6-indolyzinyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), quinolyl (e.g., 8-quinolyl), isoquinolyl (e.g., 3-isoquinolyl), acridyl (e.g., 1-acridyl), phenanthrydinyl (e.g., 2-phenanthrydinyl, 3-phenanthrydinyl), pyridazinyl (e.g., 3-pydidazinyl), pyrimidinyl (e.g., 4-pyrimidinyl), pyrazinyl (e.g., 2-pyrazinyl), cinnolinyl (e.g., 3-cinnolinyl), phthaladinyl(e.g., 5-phthaladinyl), quinazolinyl (e.g., 2-quinazolinyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl), benzisoxazolyl (e.g., 1,2-benzisoxazol-4-yl, 2,1-benzisoxazol-3-yl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), benzoxazolyl (e.g., 2-benzoxazolyl), benzoxadiazolyl (e.g., 4-benzoxadiazolyl), isothiazolyl (e.g., 3-isothiazolyl, 4-isothiazolyl) benzisothiazolyl (e.g., 1,2-benzisothiazol-3-yl, 2,1-benzisothizol-5-yl), thiazolyl (e.g., 2-thiazolyl), benzothiazolyl (e.g., 2-benzothiazolyl), thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl), oxadiazolyl (e.g., 1,3,4-oxadiazol-2-yl), dihydroxadiazolyl (e.g., 4,5-dihydro-1,2,4-oxadiazol-3-yl), furyl (e.g., 2-furyl, 3-furyl), benzofuryl (e.g., 3-benzofuryl), isobenzofuryl (e.g., 1-isobenzofuryl), thienyl (e.g., 2-thienyl, 3-thienyl), benzothienyl (1-benzothiophen-2-yl, 2-benzothiophen-1-yl), tetrazolyl (e.g., 5-tetrazolyl), benzodioxolyl (e.g., 1,3-benzodioxol-5-yl), dibenzofuryl (e.g., 2-dibenzofuryl, 3-dibenzofuryl), dibenzoxepinyl (e.g., dibenz[b,f]oxepin-2-yl), dihydrodibenzoxepinyl (e.g., dihydrodibenz[b,f]oxepin-2-yl, chromenyl (e.g., 2H-chromen-3-yl, 4H-chromen-2-yl), dibenzothiepinyl (e.g., dibenzo[b,f]thiepin-3-yl, dihydrodibenzo[b,f]thiepin-3-yl), morpholinyl (e.g., 1,4-morpholin-4-yl), phenothiadinyl (2-phenothiadinyl), cyclopentathienyl (e.g., cyclopenta[b]thiophen-3-yl), cyclohexathienyl (e.g., cyclohexa[b]thiophen-3-yl), and the like.
The term xe2x80x9ccycloalkylxe2x80x9d means C3-C8 cyclic alkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
The term xe2x80x9ccycloalkenylxe2x80x9d means C3-C8 cyclic alkenyl, for example, cyclopropenyl (e.g., 1-cyclopropenyl), cyclobutenyl (e.g., 2-cyclobuten-1-yl), cyclopentenyl (1-cyclopenten-1-yl), cyclohexenyl (1-cyclohexen-1-yl), and the like.
The term xe2x80x9ccycloalkylxe2x80x9d means C1-C6 alkoxy, for example, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, and the like.
Examples of the substituted amino in the definition of xe2x80x9csubstituted- or un-substituted-aminoxe2x80x9d include mono- or di-substituted amino such as methylamino, ethylamino, dimethylamino, cyclohexylamino, phenylamino, diphenylamino, or cyclic amino such as piperidino, piperadino or morpholino.
The term xe2x80x9cacyloxyxe2x80x9d means an acyloxy derived from the xe2x80x9cacylxe2x80x9d above, for example, acetyloxy, propionyloxy, butyryloxy, valeryloxy, and the like.
The term xe2x80x9chalogenxe2x80x9d means fluorine, chlorine, bromine and iodine.
The term xe2x80x9calkoxycarbonylxe2x80x9d means an alkoxycarbonyl group derived from the xe2x80x9calkoxyxe2x80x9d above, for example, methoxycarbonyl, ethoxycarbonyl, phenyloxycarbonyl, and the like.
The term xe2x80x9caralkyloxycarbonylxe2x80x9d means an aralkyloxycarbonyl group derived from the xe2x80x9caralkylxe2x80x9d above, for example, benzyloxycarbonyl, phenethyloxycarbonyl, and the like.
The term xe2x80x9caryloxycarbonylxe2x80x9d means an aryloxycarbonyl group derived from the xe2x80x9carylxe2x80x9d above, for example, phenyloxycarbonyl, naphtyloxycarbonyl, and the like.
The term xe2x80x9calkenyloxyxe2x80x9d means an alkenyloxy group derived from the xe2x80x9calkenylxe2x80x9d above, for example, vinyloxy, 1-propenyloxy, 2-butenyloxy, and the like.
The term xe2x80x9chydroxyalkylxe2x80x9d means a hydroxyalkyl group derived from the xe2x80x9calkylxe2x80x9d above, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, and the like.
The term xe2x80x9calkylthioxe2x80x9d means an alkylthio group derived from the xe2x80x9calkylxe2x80x9d above, for example, methylthio, ethylthio, propylthio, and the like. The term xe2x80x9calkylenedioxyxe2x80x9d means C1-C3 alkylenedioxy, for example, methylenedioxy, ethylenedioxy, propylenedioxy, and the like.
In the case of xe2x80x9cphenylene, xe2x80x9cnaphtylenexe2x80x9d, xe2x80x9cthiophenediylxe2x80x9d, xe2x80x9cindolediylxe2x80x9d, xe2x80x9coxazolediylxe2x80x9d, xe2x80x9coxadiazolediylxe2x80x9d and tetrazolediylxe2x80x9d, the said group can bind to the neighboring groups at any two substitutable sites.
In the definitions above, when a substituent(s) is cyclic, it may be substituted by one to three substituents selected from nitro, alkoxy, sulfamoyl, substituted- or un-substituted-amino, acyl, acyloxy, hydroxy, halogen, alkyl, alkynyl, carboxy, alkoxycarbonyl, aralkoxycarbonyl, aryloxycarbonyl, mesyloxy, cyano, alkenyloxy, hydroxyalkyl, trifluoromethyl, alkylthio, xe2x80x94Nxe2x95x90PPh3, oxo, thioxo, hydroxyimino, alkoxyimino, phenyl and alkylenedioxy. The substituent(s) may bind to any substitutable positions on the ring.
Examples of salts of the compound (I) include those formed with an alkali metal (e.g., lithium, sodium or potassium), an alkali earth metal (e.g., calcium), an organic base (e.g., tromethamine, trimethylamine, triethylamine, 2-aminobutane, t-butylamine, diisopropylethylamine, n-butylmethylamine, cyclohexylamine, dicyclohexylamine, N-isopropylcyclohexylamine, furfurylamine, benzylamine, methylbenzylamine, dibenzylamine, N,N-dimethylbenzylamine, 2-chlorobenzylamine, 4-methoxybenzylamine, 1-naphthylenemethylamine, diphenylbenzylamine, triphenylamine, 1-naphthylamine, 1-aminoanthoracene, 2-aminoanthoracene, dehydroabiethylamine, N-methylmorpholine or pyridine), an amino acid (e.g., lysine, or arginine), and the like.
The term xe2x80x9chydratexe2x80x9d means a hydrate of the compound of the formula (I) or its salt. Examples include mono- and dihydrates.
The present compounds are shown by the formula (I) and are inclusive of the form of any types of stereoisomers (e.g., diastereomer, epimer, enantiomer) and racemic compounds.
Among the compounds of the general formula (I), those wherein m=1, especially, those shown in Tables 3b and 3c below are known compounds described in Japanese Patent Publication (KOKAI) No. 180862/1990.
Among the compounds of the general formula (I), those wherein m=0, [i.e., those shown by the general formula (Ixe2x80x2)], can be prepared by reacting an amino compound of the general formula (II) with a reactive derivative of sulfonic acid or carboxylic acid corresponding to the partial structure: Zxe2x80x94X1xe2x80x94X2xe2x80x94X3 as shown below. 
Wherein A, B, R, X1, X2, X3, Y and Z are as defined above.
A sulfonic acid corresponding to the partial structure: Zxe2x80x94X1xe2x80x94X2xe2x80x94X3 is a compound of the general formula X3xe2x80x94X2xe2x80x94X1xe2x80x94SO2OH and a carboxylic acid corresponding to the said partial structure is a compound of the general formula X3xe2x80x94X2xe2x80x94X1xe2x80x94COOH. Reactive derivative of these sulfonic or carboxylic acids means a corresponding halide (e.g., chloride, bromide, iodide), acid anhydride (e.g., mixed acid anhydride with formic acid or acetic acid), active ester (e.g., succinimide ester), and examples thereof generally include acylating agents used for the acylation of amino group. The carboxylic acid X3xe2x80x94X2xe2x80x94X1xe2x80x94COOH can be used in the reaction as it is without converting into a reactive derivative, in the presence of a condensing agent (e.g., dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimetylaminopropyl)carbodiimide, N,Nxe2x80x2-carbonyldiimidazole) which are used in the condensing reaction between amine and carboxylic acid.
The reaction can be conducted under the conditions generally used for the. acylation of amino group. For example, in the case of condensation using an acid halide, the reaction is carried out using a solvent such as an ether solvent (e.g., diethylether, tetrahydrofuran, dioxane), benzene solvent (e.g., benzene, toluene, xylene), halogenated hydrocarbon solvent (e.g., dichloromethane, dichloroethane, chloroform), ethyl acetate, dimethylformamide, dimethyl sulfoxide, acetonitrile, or the like, if necessary, in the presence of a base (e.g., organic base such as triethylamine, pyridine, N,N-dimethylaminopyridine, N-methylmorpholine; inorganic base such as sodium hydroxide, potassium hydroxide, potassium carbonate, or the like) under cooling, at room temperature or under heating, preferably at temperature ranging from xe2x88x9220xc2x0 C. to a temperature under cooling, or from room temperature to a refluxing temperature of the reaction system, for several min to several hr, preferably for 0.5 hr to 24 hr, more preferably, for 1 hr to 12 hr.
The reaction conditions for the reaction between other reactive derivative or a free acid and an amine (II) can be determined in a conventional manner depending on the characteristics of the respective reactive derivative or free acid.
The reaction product can be purified by conventional purification methods, for example, the extraction with a solvent, chromatography, recrystallization, or the like.
Specific examples of the compound (II) as a starting material for the present method are as follows. Examples of 3-amino[2.2.1]bicyclic compound include 7-(3-aminobicyclo[2.2.1]hept-2-yl)-5-heptenoic acid, 7-(3-aminobicyclo[2.2.1]hept-2-yl)-2,2-dimethyl-5-heptenoic acid, 7-(N-metnyl-3-aminobicyclo[2.2.1]hept-2-yl)-5-heptenoic acid, 6-(3-aminobicyclo[2.2.1]hept-2-yl)-5-hexenoic acid. Specific examples of 2-amino-6,6-dimethyl[3.1.1]bicyclic compound include 7-(2-amino-6,6-dimethylbicyclo[3.1.1]hept-3-yl)-5-heptenoic acid. In these starting compounds, the heptenoic acid chain may be saturated to form heptanoic acid chain, intervened by a hetero atom(s) or a hetero group(s) such as xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, or a phenylene(s), or substituted with an oxo group. Examples of such compounds include 7-(3-aminobicyclo[2.2.1]hept-2-yl)heptanoic acid, 4-[2-(2-aminobicyclo[3.1.1]hept-3-yl)ethoxyphenylacetic acid, 7-(3-aminobicyclo[2.2.1]hept-2-yl)-6-oxo-heptanoic acid. These starting compounds are either described in the Japanese Patent Publication (KOKOKU) No. 79060/1993 or 23170/1991, or can be prepared according to the method described therein.
Sulfonic acid X3xe2x80x94X2xe2x80x94X1xe2x80x94SO2OH and carboxylic acid X3xe2x80x94X2xe2x80x94X1xe2x80x94COOH corresponding to the partial structure Zxe2x80x94X1xe2x80x94X2xe2x80x94X3 mean a sulfonic acid or carboxylic acid having substituents corresponding to the Xs above. That is, examples include alkane-sulfonic acid or -carboxylic acid, alkene-sulfonic acid or -carboxylic acid, alkyne-sulfonic acid or -carboxylic acid, cycloalkane-sulfonic acid or -carboxylic acid, cycloalkene-sulfonic acid or -carboxylic acid, aryl-sulfonic acid or -carboxylic acid, aralkyloxy-sulfonic acid or -carboxylic acid, heterocyclic-substituted-sulfonic acid or -carboxylic acid, heteroarylalkyl-sulfonic acid or -carboxylic acid, and substituted-amino-sulfonic acid or -carboxylic acid. Each of sulfonic and carboxylic acids may have a substituent(s) above. These sulfonic acids and carboxylic acids are commercially available or can be easily synthesized from a known compound(s) in accordance with a known method. Upon reaction, the sulfonic or carboxylic acid can be converted into the corresponding reactive derivative above, if necessary. For example, when an acid halide is needed, the compound is reacted with thionyl, halide (e.g., thionyl chloride), phosphorous halide (e.g., phosphorous trichloride, phosphorous pentachloride) or oxalyl halide (e.g., oxalyl chloride) in accordance with a known method such as those described in a literature (e.g., Shin-Jikken-Kagaku-Koza, vol. 14, pp. 1787 (1978); Synthesis, 852-854 (1986); Shin-Jikken-Kagaku-Koza, vol. 22, pp. 115 (1992)). The other reactive derivatives can also be prepared in accordance with a known method.
Among the objective compounds (I), those wherein the side chain A contains an unsaturated bond, especially, a double bond, can also be prepared by reacting an aldehyde derivative of the general formula (III) below with an ylide compound corresponding to the rest part of the side chain Axe2x80x94R under the conditions for the Wittig reaction: 
wherein A, B, R, X1, X2, X3, Y and Z are as defined above.
The starting compound (III) can be prepared in accordance with a method described in, for example, Japanese Patent Publication (KOKAI) No. 256650/1990. Further, an ylide compound corresponding to the rest part of the side chain Axe2x80x94R can be synthesized by reacting triphenylphosphine with a corresponding halogenated alkanoic acid, or an ester derivative, ether derivative or amide derivative thereof in the presence of a base according to a known method.
Among the objective compounds (I), those wherein R is COOH can be converted into a corresponding ester derivative, alcohol fare derivative, ether derivative, amide derivative, if desired. For example, ester derivatives can be prepared by esterifying a carboxylic acid in a conventional manner. An ester derivative, when reduced, gives an alcohol derivative, and amidated, gives an amide derivative. An ether derivative can be obtained by O-alkylating an alcohol derivative.
The compound (I) of the present invention shows antagonistic effect against PGD2 in vitro through the binding to PGD2 receptor, and is useful as a drug for treating diseases in which mast cell dysfunction due to excessive production of PGD2 is involved. For example, the compound (I) is useful as a drug for treating diseases, such as systemic mastocytosis and disorder of systemic mast cell activation, and also tracheal contraction, asthma, allergic rhinitis, allergic conjunctivitis, urticaria, injury due to ischemic reperfusion, and inflammation. The compound (I) shows preventive effect on nasal occlusion in vivo, and therefore is especially useful as a drug for treating them.
When using a compound (I) of the present invention in treatment, it can be formulated into ordinary formulations for oral and parenteral administration. A pharmaceutical composition containing a compound (I) of the present invention can be in the form for oral and parenteral administration. Specifically, it can be formulated into formulations for oral administration such as tablets, capsules, granules, powders, syrup, and the like; those for parenteral administration such as injectable solution or suspension for intravenous, intramuscular or subcutaneous injection, inhalant, eye drops, nasal drops, suppositories, or percutaneous formulations such as ointment.
In preparing the formulations, carriers, excipients, solvents, and bases known to one ordinary skilled in the art may be used. In case of tablets, they are prepared by compressing or fomulating an active ingredient together with auxiliary components. Examples of usable auxiliary components include pharmaceutically acceptable excipients such as binders (e.g. cornstarch), fillers (e.g., lactose, microcrystalline cellulose), disintegrants (e.g., starch sodium glycolate) or lubricants (e.g., magnesium stearate). Tablets may be coated appropriately. In the case of liquid formulations such as syrups, solutions, or suspensions, they may contain suspending agents (e.g., methyl cellulose), emulsifiers (e.g., lecithin), preservatives, and the like. In the case of injectable formulations, it may be in the form of solution or suspension, or oily or aqueous emulsion, which may contain suspension-stabilizing agent or dispensing agent, and the like. In the case of an inhalant, it is formulated into a liquid formulation applicable to an inhaler. In the case of eye drops, it is formulated into a solution or a suspension. Especially, in the case of nasal drug for treating nasal occlusion, it can be used as a solution or suspension prepared by a conventional formulating method, or as a powder formulated using a powdering agent (e.g., hydroxypropyl cellulose, carbopole), which are administered into the nasal cavity. Alternatively, it can be used as an aerosol after filling into a special container together with a solvent of lowboiling point.
Although an appropriate dosage of the compound (I) varies depending on the administration route, age, body weight, sex, or conditions of the patient, and the kind of drug(s) used together, if any, and should be determined by the physician in the end, in the case of oral administration, the daily dosage can generally be between about 0.01-100 mg, preferably about 0.01-10 mg, more preferably about 0.1-10 mg, per kg body weight. In the case of parenteral administration, the daily dosage can generally be between about 0.001-100 mg, preferably about 0.001-1 mg, more preferably about 0.01-1 mg, per kg body weight. The daily dosage can be administered in 1-4 divisions.